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FORMULATION AND EVALUATION OF PREDNISOLONE SODIUM

PHOSPHATE ORALLY DISINTEGRATED TABLETS

A Dissertation Submitted to

THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSTIY, CHENNAI

In partial fulfillment for the award of degree of

MASTER OF PHARMACY

IN

PHARMACEUTICS

Submitted by

Reg. No.: 26107707

Under the Guidance of

Dr. M. Senthil Kumar, M. Pharm, Ph.D.,

Principal & Head of the Department,

Department of Pharmaceutics

ANNAI VEILANKANNIS PHARMACY COLLEGE

SAIDAPET, CHENNAI 600 015.

SEPTEMBER - 2012.

DECLARATION

I hereby declare that the dissertation work entitled FORMULATION AND

EVALUATION OF PREDNISOLONE SODIUM PHOSPHATE ORALLY

DISINTEGRATED TABLETS is based on the original work carried out by me in

Annai Veilankannis Pharmacy College, Saidapet, Chennai and Formulation R&D,

Scoat pharmaceutical Pvt Ltd., Hyderabad under the guidance of Dr. M.Senthil

Kumar and coguidance of Mr.J.Subba reddy , for submission to The Tamilnadu

Dr.M.G.R University in the partial fulfillment of the requirement for the award of

degree Master of Pharmacy in Pharmaceutics. The work is original and has not been

submitted in part or full for any other diploma or degree of this or any other

university. The information furnished in this dissertation is genuine to the best of my

knowledge and belief.

Chennai,

21.08.2012 26107707

Acknowledgement

At the outset, I thank the God who brought this opportunity, gave me the abundance

of requisite determination and strength to pursue and complete this course and dissertation

successfully. It is my immense pleasure privileges to acknowledge the untold contributions,

thankfully received, the blessed inspiration and the unreserved support I have had from the

individual and institutional sources with whom I have been in association during the course

of my last two years of pursuit I hereby take this opportunity to acknowledge all those who

have helped me in the completion of this dissertation work.

I am extremely grateful to Dr. S.Devaraj, Chairman and Mr. Devanad, secretary

Annai Veilankannis Pharmacy College , saidapet, Chennai 600015 for providing me

the opportunity to do my project at MSN Laboratories Ltd., Hyderabad.

Its a fact that every mission needs a spirit of hard work and dedication but it needs to

be put on the right path to meet its destination and in my case this credit goes to my respected

teacher and guide, Dr.M.Senthil Kumar, principal , Department of pharmaceutics,

AnnaiVeilankannis Pharmacy College. I am very much thankful to him for his inspiration,

kind co-operation, caring attitude, timely help, valuable guidance and constant

encouragement during every phase of this dissertation. His patience way of sharing

knowledge, our numerous discursions support always propelled and boosted me to perform

better. I would remain grateful to him.

My sincere and heartful thanks to my teachers, Dr.M.Senthil kumar,

Mrs.S.Valarmathi for their help and co-operation.

I am extremely grateful to Mr.J.Subba reddy, Manager, Formulation R&D,

department for providing me the opportunity to do my project at MSN Laboratories Ltd.,

Hyderabad.

I am indebted to industrial guide Mr.J.Subba reddy, Manager, Formulation R&D,

MSN Laboratories Ltd., Hyderabad for allowing me to accomplish the project work in this

industry. He was always there with his enthusiastic suggestions and corrections, despite of

his extremely busy schedule rendered me the freedom to explore the facilities in the

laboratory and utilize them up to my learning capabilities. His innovative ideas helped me to

successfully complete my project and my thesis work with spontaneity and enthusiasm.

I profoundly express my sincere thanks to Mr.J.Subba reddy, Manager ,

Formulation R&D, MSN Laboratories Ltd., Hyderabad for their valuable suggestions and

kind encouragement during the dissertation work.

I would also like to extend my sincere thanks to the entire staff of the

Annaiveilankannis pharmacy college., saidapet, Chennai, formulation department, MSN

Laboratories Ltd., Hyderabad.

I would like to thank my friends Raja lakshmi, Balakrishna, Dinesh , Ashok,

Srinivasrao, Hariharan, Anusha, Raghunath, and Suresh for their co-operation and help in

carrying out my project work.

I thank everyone who helped me directly or indirectly in the successful completion of

this dissertation.

And at last but not least my heartiest and dearest gratitude to my lovable friends ,

sadhana,sujith and my brother,sister for their love, faith, care and support. And to my

beloved friends Srinivas naidu, Sudheer, mohan and Marshal.

I would like to express my deep sense of love and affection to my family members

especially to my FATHER ,MOTHER my beloved brothers and sisters for their strong piety

and pantheism enable me to face the world without fear and with pedantic strength.

CONTENTS

S.NO PARTICULARS PAGE

NO

1. INTRODUCTION 01

2. REVIEW OF LITERATURE 29

3. AIM AND OBJECTIVE 34

4. PLAN OF WORK 35

5. MATERIALS AND METHODS 36

6. DRUG PROFILE 43

7. RESULTS 88

8. DISCUSSION 95

9. SUMMARY CONCLUSION 98

10. BIBILOGRAPHY 100

List of tables

S.no Particulars Page no

1.

Orally disintegrating tablet manufacturers and technology characteristics: 15

2. Excipients and their uses in freeze drying technique 17

3. Classification of superdisintegrants 26

4. Instrument list. 36

5. Materials list 37

6. Innovator product details: 38

7. Processing problems and there remidies 38

8. Flow properties of powder. 41

9. Applications in pharmaceutical formulation or technology. 55

10. Solubility of commercially available polymethacrylates in various solvents. 56

12 Solubility of mannitol. 58

13 Uses of sodium bicarbonate. 63

14 Solubility of sodium bicarbonate. 64

15 Drug- compatibility studies: 68

16 Physical parameters of api. 70

17 Particle size analysis. 71

18. Drug solubility study (ph 1-7).

71

19. Formulation of prednisolone odt ( 30mg ) 75

20. Evaluation of tablets 88

21.

Taste evaluation (palatability study) for formulation containing mint

flavor: 89

22. Dissolution profie of orapred odt (30mg) 89

LIST OF FIGURES

S.NO PARTICULARS PAGE

NO

1. Process principle for formation of agglomerates 20

2. Dissolution profile of ORAPRED ODT in Water. 90

3. Dissolution profile of ORAPRED ODT in 0.1N Hcl. 90

4. Dissolution profile of ORAPRED ODT in 4.5 Acetate buffer. 91

5. Dissolution profile of ORAPRED ODT in different media. 91

6. Dissolution profile of Formulations F-3, F-4, F-5, and F-6. 93

7. Dissolution profile of Formulations F-7, F-8, F-9, and F-10. 93

8. Dissolution profile of Formulations F-11, F-12, and F-13. 94

9. Dissolution profile of ORPRED and Formulation F-12. 94

Introduction

Dept of Pharmaceutics, Annai veilankannis pharmacy college, chennai 1

INTRODUCTION

Tablets

Tablets may be defined as solid pharmaceutical dosage forms containing drug

substances with or without suitable diluents and prepared either by compression or

molding methods. They have been in widespread use since the latter part of the 19th

century and their popularity continues. The term compressed tablet is believed to have

been first used by JOHN WYETH and Brother of PHILADELPHIN. During the same

period molded tablets were introduced to be used as Hypodermic tablets for injections.

Tablets remain popular as oral dosage form because of the advantages, afforded

both to the manufacturer [e.g.: simplicity & economy of preparation, stability and

convenience in packing, shipping, and dispensing] and the patient [e.g.: accuracy of

dosage, compactness, post ability, blandness of taste and ease of administration.

Although tablets are more frequently discoid in shape, they also may be round,

oval, oblong, cylindrical or triangular. They may differ greatly in size and weight

depending on the amount of drug substance present and the intended method of

administration.

Properties of tablets

The attributes of an acceptable tablet are as follows:

The tablet must be sufficiently strong and resistance to shock and abrasion and to

withstand handling during manufacturing, packaging, shipping and use. Hardness

and friability tests measure this property.

Tablet must be uniform in weight and in drug content of the individual tablet.

This is measured by the weight variation and content uniformity tests.

The drug content of the tablet must be bioavailable. This property is measured by

the dissolution test. Accurate bioavailability can be obtained from the drug levels

of the drug after its administration.

Tablets must be elegant in appearance and must have characteristic shape, color

and other markings necessary to identify the product.

Tablets must retain all these functional attributes, which include drug stability and

efficacy.

Introduction


Advantages of Tablets:

They are easy to be administered

They offer the greater capabilities of all oral dosage forms for the greatest dose

precision and the least content variability.

Their cost is lowest of all oral dosage forms.

They are the lightest and most compact of all oral dosage forms.

Product identification is potentially the simplest and cheapest, requiring no

additional processing steps when employing an embossed or monogrammed

punch face.

They are in general the easiest and cheapest to package and ship of all oral dosage

forms.

They may provide the greatest ease of swallowing with the least tendency for

hang-up above the stomach.

They lend themselves to certain special release profile products, such as enteric or

delayed release products.

They are better suited to large-scale production than other unit oral forms.

They have the best-combined properties of chemical, mechanical and

microbiological stability of all the oral forms.

One of the major advantages of tablet over capsules is that the tablet is essentially

tamperproof dosage form.

Disadvantages of Tablets:

Some drugs resist compression into dense compacts, owing to their amorphous

nature or flocculent, low-density character.

Drugs with poor wetting, slow dissolution properties, intermediate to large

dosages, or any combination of these features may be difficult or impossible to

zormulate and manufacture as a tablet that will still provide adequate or full drug

bioavailability.

Introduction


Bitter tasting drugs, drugs with objectionable odor or drugs that the sensitive to

oxygen or atmosphere moisture may require encapsulation or a special type of

coating with may increase the most of the finished tablets.

A major disadvantage of capsules over tablets is their higher cost.

Types of tablets

Tablets are classified according to their route of administration or function. The

following are the 5 main classification groups:

Tablets ingested orally

1. Compressed tablets

2. Multiple compressed tablets

3. Multilayered tablets

4. Sustained action tablets

5. Enteric coated tablets

6. Sugar coated tablets

7. Film coated tablets

8. Chewable tablets

Tablets used in the oral cavity

1. Buccal tablets

2. Sublingual tablets

3. Lozenge tablets and torches

4. Dental cones

Tablets administered by other routes

1. Implantation tablets

2. Vaginal tablets

Tablets used to prepare solutions

1. Effervescent tablets

Molded tablets or tablet triturates (TT)

1. Dispensing tablets (DT)

2. Hypodermic tablets (HT)

Introduction


Compressed tablets:

These tablets are uncoated and made by compression of granules. These tablets

are usually intended to provide rapid disintegration and drug release. These tablets

contain water-soluble drugs, which after swallowing get disintegrated in the

stomach, and its drug contents are absorbed in the gastrointestinal tract and distribute in

the whole body.

Multiple compressed tablets (MCT):

These tablets are prepared to separate physically or chemically incompatible

ingredients or to produce repeat action prolonged action products. To avoid

incompatibility, the ingredients of the formulation except the incompatible materials are

compressed into a tablet then incompatible substances along with necessary excipients

are compressed tablet.

Multilayered tablets:

These tablets consist of two or more layer of materials compressed successively in

the same tablets. The color of each layer may be the same or different. The tablets having

layers of different colors are known as multicolored tablets.

Sustained action tablets:

These tablets are used to get a sustained action of medicament. These tablets

when taken orally release the medicament in a sufficient quantity as and when required

maintaining the maximum effective concentration of the drug in the blood through out

the period of treatment.

Enteric-coated tablets (ECT):

These are compressed tablets meant for administration by swallowing and are

designed to bypass the stomach and get disintegrated in the intestine only. These tablets

are made to release the drug undiluted and in the highest concentration possible within

the intestine. e.g.: tablets containing antihelmentics and amoebicides.

Sugar coated tablets (SCT):

The compressed tablets having a sugar coating are called sugar coated tablets.

Such coatings may be colored and are beneficial in covering up drug substances

processing objectionable tastes or odors and protecting materials sensitive to oxidation.

Introduction


Film coated tablets (FCT):

These are compressed tablets that are covered with a thin layer or a film of water-

soluble material. A number of polymeric substances with film-forming properties may be

used. Film coating imparts the same general characteristics as sugar coating, with the

added advantage of greatly reduced time period required for the coating operation and

reduced thickness of coating, these compressed tablets having some polymer substance,

such as hydroxy propyl cellulose, hydroxy propyl methylcellulose and ethyl cellulose.

Chewable tablets:

These tablets are to be chewed in the mouth and broken into small pieces. In this

way, the disintegration time is reduced and the rate of absorption of he medicament is

increased. e.g.: aluminum hydroxide tablets, and phenolphthalein tablets.

Buccal tablets:

These tablets are to be placed in the buccal pouch or between the gums and lips or

cheek where they dissolve or disintegrate slowly and are absorbed directly without

passing into the alimentary canal. e.g.: tablets of ethisterone

Sublingual tablets:

These tablets are to be placed under the tongue where they dissolve or disintegrate

quickly and are absorbed directly without passing into GIT. E.g.: tablets of glyceryl

trinities.

Lozenges and torches:

These tablets are designed to exert local effect in the mouth or throat. These

tablets are commonly used to treat sore throat or to control coughing in common cold.

They may contain local anaesthetics antiseptic, antibacterial agents, astringent and

antitussives.

Dental cones:

These are relatively minor compressed tablets meant for placing them in the

empty socket after tooth extraction. They prevent the multiplication of bacteria in the

socket following such extraction by using slow releasing antibacterial compounds or to

Introduction


reduce bleeding by containing the astringent. These cones generally get dissolved in 20 to

40 min time.

Implantation tablets:

These tablets are placed under the skin or inserted subcutaneous by means of minor

surgical operation and are slowly absorbed. These implants must be sterile and should be

packed individually in sterile condition. Implants are mainly used for administration of

hormones such as testosterone, and deoxycorticosterone etc.

Vaginal tablets:

These tablets are meant to dissolve slowly in the vaginal cavity. These tablets are

typically ovoid or pear shaped to facilitate retention in the vagina. This tablet form is

used to release steroids, antibacterial agents, antiseptics or astringents to treat vaginal

infections.

Effervescent tablets:

In addition to the drug substance, these contain sodium bicarbonate and an

organic acid such as tartaric acid or citric. In the presence of water, these additives react,

liberating carbon dioxide that acts as disintegrator and produces effervescence. Except for

small quantities of lubricants present, effervescent tablets are soluble.

Tablet triturates

Tablet triturates usually are made from moist material, using a triturate mold that

gives them the shape of cut sections of cylinder. Such tablets must be completely and

rapidly soluble. The problem arising from the compression of these tablets is the failure

to find a lubricant that is completely water-soluble.

Dispensing tablets:

These tablets provide a convenient quality of potent drug that can be incorporated

readily in to powders and liquids, thus circumventing the necessity to weigh small

quantities. These tablets are supplied primarily as a convenience for extemporaneous

compounding and should never be dispensed as a dosage form.

Hypodermic tablets:

Hypodermic tablets are soft, readily soluble tablets and originally were used for

the preparation of solutions to be injected. Since stable parenteral solutions are now

Introduction


available for most new drug substances, there is no justification for the hypodermic

tablets for injection. Their use in this manner should be discouraged, since the resulting

solutions are not sterile. Large quantities of these tablets continue to be made, but for oral

administration. No hypodermic tablets ever have been recognized by the official

compendia.

Tablets and hard gelatin capsules constitute a major portion of drug delivery

systems that are currently available. However, many patient groups such as the elderly,

children and patients who are mentally retarded, uncooperative, nauseated, or on reduced-

liquid-intake diets have difficulty in swallowing these dosage forms. Elderly patients may

find the administration of these dosage forms particularly difficult because many of them

are required to consume medicines on a regular basis to maintain their quality of life.

Children also may have difficulty ingesting these dosage forms because of their

underdeveloped muscular and nervous systems. Swallowing conventional tablets can be

further hindered by conditions such as allergic reactions, and episodes of coughing1.

The aforementioned problems can be solved by developing rapidly disintegrating

and dissolving tablet dosage forms for oral administration because they dissolve in saliva

and do not require water for swallowing. Oral disintegrating tablets are also called as

mouth dissolving tablets, orodispersible tablets, quick disintegrating tablets, rapid

dissolving tablets, porous tablets and rapimelts2.

Recently orally disintegrating tablet terminology has been approved by United

States Pharmacopoeias, Centre for Drug Evaluation and Research (CDER).

US FDA defined orally disintegrating tablet as A solid dosage form containing

medicinal substances, which disintegrates rapidly, usually within a matter of seconds,

when placed upon the tongue. Recently European pharmacopoeia also adopted the term

orodispersible tablet as a tablet that is to be placed in the mouth where it disperses

rapidly before swallowing3. Despite various terminologies used, orally disintegrating

tablets are here to offer unique form of drug delivery with many advantages over the

conventional dosage forms.

Introduction


ORALLY DISINTEGRATE TABLETS:

Oral drug delivery remains the preferred route for administration of various drugs.

Recent developments in the technology have prompted scientists to develop orally

disintegrate tablets (ODT) with improved patient compliance and convenience. ODTs are

solid unit dosage forms, which disintegrate or dissolve rapidly in the mouth without the

need of chewing and water. It is particularly meant for people who have difficulty in

swallowing conventional tablets and capsules. It has been reported that Dysphasia

(difficulty in swallowing) is common among all age groups and more specific with

pediatric and geriatric populations along with institutionalized patients and patients with

nausea, vomiting, and motion sickness complications. ODTs with good taste and flavor

increase the acceptability of bitter drugs by various groups of population1.

Orally disintegrating tablets are also called as orodispersible tablets, quick

disintegrating tablets, mouth dissolving tablets, fast disintegrating tablets, fast dissolving

tablets, rapid dissolving tablets, porous tablets and rapimelts. However, of all the above

terms, United States pharmacopoeia (USP) approved these dosage forms as ODTs.

Recently, European Pharmacopoeia has used the term orodispersible tablets that disperse

readily and within 3 min in mouth before swallowing.

USFDA defined ODT as A solid dosage form containing medical substance or

active ingredient which disintegrates rapidly usually within a matter of seconds when

placed upon the tongue. The disintegration time for ODTs generally ranges from several

seconds to about a minute.

Typically a dispersible tablet is dispersed in about 5-15 ml of water (e.g. in a

tablespoonful or a glass of water) and the resulting dispersion is administered to the

patient. However, they can also be placed directly on the tongue and sucked. Dispersible

tablets are required to disintegrate within 3 mins in water at 15-25C. Also the dispersion

produced from a dispersible tablet should pass through a sieve screen with a nominal

mesh aperture of 710 microns. The dispersion properties of dispersible tablets can be

facilitated by the inclusion of an acid/base couple in which the base liberates carbon

dioxide when the components of the couple are dissolved in water.

Introduction


Ideal characteristics of dispersible tablets

They require water or other liquid at the time of administration.

Should easily disintegrate and dissolve.

Mask or overcome unacceptable taste of drug.

They should have high drug loading.

They should have pleasant feel in the mouth.

They should have low sensitivity against environmental conditions like moisture,

temperature etc.

Ease of administration for patients who are mentally ill, disabled and

uncooperative.

Should be portable without fragility concern.

They should be manufactured using conventional tablet processing and packaging

equipment at low cost.

Special features of dispersible tablets

Dispersible tablets are not intended to be chewed or swallowed whole. They

should not be dispersed in carbonated drinks or milk due to foaming or slow

dispersion. The purpose of dispersible tablet is to provide a unit dosage form of

medication which can be easily administered to infants and children or to elderly,

who may have difficulty swallowing a tablet intact.

Advantages of dispersible tablets

They are particularly suitable both for elderly persons with swallowing difficulties

and for children.

Rapid disintegration and absorption of drug, which will produce quick onset on

action.

Certain dispersible tablets can also be divided.

The bitter taste of the active substance must be masked in advance.

Owing to the number of possible applications, the patient compliance is

improved.

Introduction


These are convenient to carry, easy to manufacture and more stable.

Quick absorption from the gastrointestinal tract improves bioavailability and

reduces unwanted effects caused by the drug. e.g. gastrointestinal irritation caused

by nonsteroidal anti inflammatory drugs.

New business opportunities like product differentiation, line extension and life

cycle management. Exclusivity of product promotion.

Although chewable tablets have been on the market for some time, they are not

same as the new dispersible tablets. Patients for whom chewing is difficult or

painful can use these new tablets easily. Dispersible tablets can be used easily in

children who have lost their primary teeth, but do not have full use of their

permanent teeth.

Limitation of dispersible tablets

One common limitation of these formulations is settling of the insoluble solids at

the bottom or sides of container of the prepared dispersion, which may lead to a

loss of part of the drug during administration, resulting in suboptimal dosing.

Disadvantages of dispersible tablets

Most dispersible tablets lack the mechanical strength common to traditional

tablets. Many products are very light weight and fragile requiring them to be

individually packaged. Patients should be advised not to push these tablets

through the foil film, but instead, peel the film back to release the fast dissolving

tablet.

Due to the formulation of dispersible tablets which also more susceptible to

degradation via temperature and humidity. Some of the newest dispersible tablet

formulations are dispensed in a conventional stock bottle. Pharmacists are advised

to take care when dispensing such formulations to ensure they are exposed to high

levels of moisture or humidity. Excess handling of tablets can introduce enough

moisture to initiate dissolution of the tablet matrix.

Introduction


Developmental challenges in dispersible drug delivery

Ease of administration

Fast Dissolving Delivery Systems are easy to administer and handle hence, leads

to better patient compliance. Usually, elderly people and pediatrics experience

difficulty in swallowing the conventional dosage forms (tablets, capsules,

solutions and suspensions) because of tremors of extremities and dysphasia. Fast

Dissolving Delivery Systems may offer a solution for these problems.

Taste of the active ingredient

Some drugs have relatively no taste, and simply adding a suitable flavor can hide

any unpleasant sensation. However, most drugs do require taste masking if they

are to be incorporated into dispersible formulations. Numerous methods exist to

achieve this, including simple wet granulation or roller compression with other

excipients to minimize the presented surface area of the drug. Spray drying can

also be employed to shroud the drug. If further taste masking is needed, the

resultant particle can be sealed with a suitable coating material (like

hydroxypropyl methyl cellulose, ethylcellulose, methacrylate and

polyvinylpyrollidone). The choice of coating material will determine the

mechanism of taste masking. In addition, the quantity of coat applied, how it is

applied, and where other excipients are included in the coating will all affect the

quality of taste masking.

Cyclodextrins (cyclic linked oligosaccharides) have been shown to prove some

measure of taste masking by trapping the drug within the cyclic structure long

enough to render initial dissolution. Other taste masking methods namely coating

methods including electrochemical, hot melt and supercritical fluids.

Encapsulation using coacervation has also been employed to encapsulate certain

drugs.

Dose

Molecules requiring high doses present challenges to development of dispersible

dosage forms: 1) Taste masking of active ingredient, 2) mouth-feel or grittiness

Introduction


and 3) tablet size. These challenges are not unrelated because most drugs will

require taste masking. It depends on the degree of bitterness relative to the dose of

the drug, which will in turn effect the final tablet size. As mentioned previously,

drug may require coating, which will result in an increase in the particle size. The

extent to which this increase will affect the mouth feel and tablet size will depend

on the dose of the drug and the amount of coating material required masking its

taste.

Hygroscopicity

Several fast dissolving tablets are hygroscopic and cannot maintain physical

integrity under normal conditions of temperature and humidity. Hence they need

protection from humidity that calls for specialized product package.

Friability

In order to allow dispersible tablets to disintegrate rapidly in the mouth, they are

made of either very porous or soft molded matrices or compressed into tablets

with low compression force, which makes the tablet friable and/or brittle which

are difficult to handle, often require specialized peel-off blister packing.

Mouth feel

Mouth feel is critical, and patients should receive a product that feels

pleasant. Any large particles from the disintegrating tablet that are insoluble

or slowly soluble in saliva would lead to an unpleasant gritty feeling. This can

be overcome by keeping the majority of the particles below the detectable size

limit. In some cases, certain flavors can imbibe an improved mouth feel

perception, resulting in a product that is perceived as being less gritty, even if

the only change is the flavor. Effervescence can be added to aid disintegration

and improve mouth feel by reducing the dryness of a product.

Introduction


SIGNIFICANCE2:

ODTs offer all advantages of solid dosage forms along with special advantages,

include:

As ODTs are unit solid dosage forms, they provide good stability, accurate

dosing, easy manufacturing, small packaging size, and easy to handle by patients.

Rapid disintegration of tablet results in quick dissolution and rapid absorption which

provide rapid onset of action.

Medication as bitter pill has changed by excellent mouth feel property produced

by use of flavors and sweeteners in ODTs.

Bioavailability of drugs that are absorbed from mouth, pharynx, and esophagus is

increased.

Pre-gastric absorption of drugs avoids hepatic metabolism, which reduces the

dose and increases the bio-availability.

Selection of ODT drug candidates3

Several factors must be considered when selecting drug candidates for delivery as

ODT dosage forms. In general, an ODT is formulated as a bioequivalent line extension of

an existing oral dosage form. Under these circumstances, it is assumed that the absorption

of a drug molecule from the ODT occurs in the post gastric GIT segments, similar to the

conventional oral dosage form.

It is possible that these differences may, in part, be attributed to the drug

molecule, formulation, or a combination of both. If significantly higher plasma levels and

systemic exposure have been observed, pregastric absorption leading to the avoidance of

first-pass metabolism may play an important role. This situation may have implications

for drug safety and efficacy, which may need to be addressed and assessed in a marketing

application for an ODT (13). For example, safety profiles may be improved for drugs that

produce significant amounts of toxic metabolites mediated by first-pass liver metabolism

and gastric metabolism and for drugs that have a substantial fraction of absorption in the

oral cavity and segments of the pregastric GIT.

The ideal characteristics of a drug for dissolution in the mouth and pregastric absorption

from an ODT include:

Introduction


1. No bitter taste;

2. Dose lower than 20 mg;

3. Small to moderate molecular weight;

4. Good solubility in water and saliva;

5. Partially nonionized at the oral cavity's ph;

6. Ability to diffuse and partition into the epithelium of the

upper git (log p >1, or preferably >2);

7. Ability to permeate oral mucosal tissue (15).

8. In contrast, the following characteristics may render a drug

unsuitable for delivery as an odt:

9. Short half-life and frequent dosing;

10. Very bitter or otherwise unacceptable taste because taste

masking cannot be achieved;

11. Require controlled or sustained release.

12. The drug dose must be lower than 400 mg for insoluble drugs

and less than 60 mg for soluble drugs (because they dissolve

quickly, odts cannot provide controlled or sustained release,

except those that contain slow-dissolving, microparticulate-

coated drugs, which quickly disperse and are swallowed.

Oral routes of drug absorption:

There are two permeation pathways for passive drug transport across the oral mucosa:

1. Paracelluloar and

2. Transcellular routes.

Descriptions of orally disintegrating dosage forms3:

Possible benefits of Orally disintegrating tablet drugs.

Clinical

1. Improved drug absorption

2. Faster onset of action

3. Minimized first-pass effect

4. Improved Bioavailability

Introduction


Medical

1. Better taste, no water needed

2. Improved stability because of unit-dose packaging

3. Manufactured with common process and conventional equipment

Orally disintegrating tablet manufacturers and technology characteristics:

Technology

In vitro

Disintegra

tion

Times

Tablet

hardness and

Robustness

Packaging

Drug-

loading

dose(mg)

Marketed

products

worldwide

Advatab (Eurand) 15-30 Hard, robust Bottles or blister

pack

Introduction


Techniques used in the formulation of dispersible tablets

The performance of dispersible tablets depends on the technology used in their

manufacture. The orally disintegrating property of the tablet is attributable to a quick

ingress of water into the tablet matrix, which creates porous structure of the tablet matrix,

which creates porous structure and results in rapid disintegration. Hence, the basic

approaches to develop dispersible tablets include maximizing the porous structure of the

tablet matrix, incorporating the appropriate disintegrating agent and using highly water-

soluble excipients in the formulation.

Following technologies have been used by various researchers to prepare fast

disintegrating tablets:

Freeze-drying or lyophilization

Tablet Molding

Direct compression

Wet granulation

Spray drying

Sublimation

Taste masking

Mass extrusion

Freeze-Drying or lyophilization

Freeze drying is the process in which water is subjected from the product after it

is frozen. This technique creates an amorphous porous structure that can dissolve rapidly.

Commonly used excipients with their uses and examples employed in formulation of

dispersible tablets using Freeze-drying are listed below in the following table. A typical

procedure involved in the formulation of dispersible tablets using this technique is

mentioned here. The active drug was dissolved or dispersed in an aqueous solution of a

carrier/polymer. The mixture dosed by weight and poured in the wells of the preformed

blister packs. The trays holding the blister packs are passed through liquid nitrogen

Introduction


freezing tunnel to freeze the drug solution or dispersion, and then the frozen blister packs

are placed in refrigerated cabinets to continue the freeze-drying. After freeze-frying the

aluminum foil backing is applied on a blister sealing machine. Finally the blisters are

packaged and shipped.

Excipients and their uses in Freeze drying technique

Excipients Use Examples

Polymer Strength and rigidity Gelatin, alginate and dextrin

Polysaccharides Crystallinity, hardness and

palatability Mannitol and sorbitol

Collapse protectants Prevents shrinking Glycerin

Flocculating agents Uniform dispersion Xanthan gum and acacia

Preservatives Prevent microbial and fungal

growth Parabens

Permeation enhancer Transmucosal permeability Sodium lauryl sulphate

pH adjusters Chemical stability Citric acid and sodium

hydroxide

Flavors and sweeteners Patient compliance -------

Water Porous unit formation -------

The freeze-drying technique has demonstrated improved absorption and increase

in bioavailability. The Zydis formulation consist of a drug physically trapped in a water-

soluble matrix (saccharine mixture and polymer), which is freeze dried to produce a

product that dissolves rapidly when placed in mouth. The ideal candidate for Zydis

Introduction


technology should be chemically stable and water insoluble and particle size preferably

less than 59 mm. Water soluble drugs might form eutectic mixtures and not freeze

adequately, so dose is limited to 60 mg and the maximum drug limit is 400 mg or water

insoluble drug as large particle sizes might present sedimentation problems during

manufacture. The major disadvantage of lyophilization technique are that it is expensive

and time consuming; fragility makes conventional packaging unsuitable for these

products and poor stability under stressed conditions.

Tablet Molding

The preparation of dispersible tablets using molding technology employs water-

soluble ingredients so that the tablet dissolves completely and rapidly. The active

ingredients in most cases are absorbed through the mucosal lining of the mouth. Molding

process is of two types i.e., solvent method and heat method. Solvent method involves

moistening the powder blend with a hydro alcoholic solvent followed by compression at

low pressures in molded plates to form a wetted mass (compression molding). The

solvent then removed by air-drying. The tablets manufactured in this manner are less

hastens dissolved. The heat molding process involves preparation of a suspension that

contains a drug, agar and sugar (e.g. Mannitol or Lactose) and pouring the suspension in

the blister packing wells, solidifying the agar at room temperature to form a jelly and

drying at 30C under vacuum. The mechanical strength of molded strength of the tablets,

need to be incorporated. Taste masking is an added problem for this technology.

Direct compression

It is the convenient way to manufacture tablets. Conventional equipment,

commonly available excipients and a limited number of processing steps are involved in

direct compression. Also high doses can be accommodated and final weight of tablet can

easily exceed that of other production methods. This technique can now be applied to

dispersible tablets because of the availability of improved tablet excipients, especially

1) Tablet disintegrants

2) Sugar-based excipients.

Introduction


1) Addition of disintegrants: Addition of disintegrants in fast dissolving tablets, leads to

quick disintegration of tablets and hence improves dissolution. In many fast dissolving

tablet technologies based on direct compression, the disintegrants principally affect the

rate of disintegration and hence the dissolution. The introduction so-called

superdisintegrants and a better understanding of their properties have increased the

popularity of this technology. Tablet disintegration time can be optimized by

concentrating the disintegrants. Below critical concentration, tablet disintegration time is

inversely proportional to disintegrants concentration. Above the critical concentration

level, however, disintegration time remains approximately constant or even increases.

Microcrystalline cellulose, cross linked carboxymethyl cellulose sodium, cross

linked polyvinyl pyrrolidone and partially substituted hydroxypropyl cellulose, though

water insoluble, absorb water and swell due to capillary action and are considered as

effective disintegrants in the preparation of dispersible tablets.

Fast disintegration of tablets can also be achieved by incorporating effervescent

disintegrating agents, which generates carbon dioxide. This phenomenon also resulted in

partial taste masking of unacceptable taste of the drug. The major drawback of

effervescent excipients is their hygroscopicity (i.e., the ability to absorb atmospheric

moisture). Hence, their manufacture requires control of humidity conditions and

protection of the final product. This is reflected by the overall cost of the product.

2) Sugar-based excipients: The alternative approach for the development of

dispersible tablets by direct compression is the use of sugar-based excipients (e.g.

dextrose, fructose, isomalt, maltose, mannitol, sorbitol, starch hydrolyse, polydextrose,

and xylitol), which display high aqueous solubility and sweetness, and hence, impart taste

masking and a pleasing mouth feel.

Wet granulation

The concept of wet granulation is well-known and conventional process for tablet

formation, used to reduced bitterness of active drug with water insoluble materials. In a

wet granulation, the material to be granulated, usually in powder forms, is wetted with an

Introduction


aqueous composition of a granulating agent to cause the powdered material to

agglomerates. This agglomerated product is subsequently dried and then milled to

reduced size in suitable form.

Wet granulation is often carried out utilizing a high-shear mixer. The high-

shear granulation process is a rapid process which is susceptible for over-wetting. Thus,

the liquid amount added is critical and the optimal amount is affected by the properties of

the raw materials. Power consumption of the impeller motor and the impeller torque have

been applied to monitor the rheological properties of the wet mass during agglomeration

and, thereby, have been used to determine the end-point of water addition. However,

these methods are affected by the equipment variables. Hence, additional process

monitoring techniques would be valuable.

Figure 1: Process principle for formation of agglomerates

Wet granulation is often carried out utilizing a high-shear mixer. The high-

shear granulation process is a rapid process which is susceptible for over-wetting. Thus,

the liquid amount added is critical and the optimal amount is affected by the properties of

the raw materials. Power consumption of the impeller motor and the impeller torque have

been applied to monitor the rheological properties of the wet mass during agglomeration

and, thereby, have been used to determine the end-point of water addition. However,

these methods are affected by the equipment variables. Hence, additional process

monitoring techniques would be valuable.

Introduction


Important steps involved in wet granulation

Mixing of drug(s) and excipients.

Preparation of binder solution.

Mixing of binder solution with powder mixture to form wet mass.

Coarse screening of wet mass using a suitable sieve (6-12 screens).

Drying of moist granules.

Screening of dry granules through a suitable sieve (14-20 screens).

Mixing of screened granules with disintegrant, glidant, and lubricant.

Limitations of wet granulation

The greatest disadvantage of wet granulation is its cost. It is an expensive

process because of labor, time, equipment, energy and space requirements.

Loss of material during various stages of processing.

Stability may be a major concern for moisture sensitive or thermo labile drugs.

Multiple processing steps give complexity and make validation and control

difficult.

An inherent limitation of wet granulation is that any incompatibility between

formulation components is aggravated.

Spray drying

Spray drying is used in pharmaceutical industries to produce highly porous powders. The

processing solvent is evaporated rapidly by spray drying, which renders the product

highly porous and thus can be used in manufacturing dispersible tablets. In this

technique, gelatin can be used as a supporting agent and as a matrix, mannitol as a

bulking agent and sodium starch glycolate or croscarmellose sodium or crospovidone are

used as superdisintegrants. Tablets manufactured from the spray dried powder have been

reported to disintegrate in less than 20 sec in aqueous medium.

Sublimation

The key to rapid disintegration for dispersible tablets is the presence of a porous

structure in the tablet matrix. Conventional compressed tablets that contain highly water-

soluble ingredients often fall to dissolve rapidly because of low porosity of the matrix.

Introduction


Hence, to generate porous matrix, volatile ingredients are used that are later subjected to

a process of sublimation. e.g. ammonium bicarbonate, ammonium carbonate, benzoic

acid, camphor, hexamethonium tetramine, naphthalene, phthalic anhydride, urea, and

urethane were compressed along with other excipients into a table. The volatile material

was then removed by sublimation, leaving behind a porous matrix. Solvents such as

cyclohexane and benzene were also suggested for the generation of porosity in the

matrix.

Taste masking

Taste masking is an essential requirement for fast dissolving tablets for

commercial success. Taste masking of the active ingredients can be achieved by various

techniques. Drugs with unacceptable bitter taste can be microencapsulated into pH

sensitive acrylic polymers. Cefuroxime axetil is microencapsulated in various types of

acrylic polymers (e.g. Eudragit E, Eudragit L-55 and Eudragit RL) by solvent

evaporation and solvent extraction techniques. These polymer microspheres showed

efficient taste masking and complete dissolution in a short period. Fine granules of drug

and disintegrant (e.g. low substituted hydroxypropyl cellulose) when coated with a water

insoluble polymer (e.g. ethylcellulose) masked the bitter taste of sparfloxacin. The

addition of low substituted hydroxypropyl cellulose as disintegrant to the drug in cores

resulted in increased dissolution rate and bioavailability of sparfloxacin compared to its

conventional tablets.

Mass extrusion

This technology involves softening the active blend using the solvent mixture of

water soluble polyethylene glycol, using methanol and expulsion of softened mass

through the extruder or syringe to get a cylinder of the product into even segments using

heated blade to form tablets. The dried cylinder can also be used to coat granules of bitter

tasting drugs and thereby masking their bitter taste.

Introduction


Role of Superdisintegrants in the manufacturing of dispersible tablets

Disintegrating agents are substances routinely included in tablet formulations and

in some hard shell capsule formulations to promote moisture penetration and dispersion

of the matrix of the dosage form in dissolution fluids. An oral solid dosage form should

ideally disperse into the primary particles from which it was prepared. Although various

compounds have been proposed and evaluated as disintegrants, relatively few are in

common usage today. Traditionally, starch has been the disintegrant of choice in tablet

formulations, and it is still widely used. For instance, starch generally has to be present at

levels greater than 5 % to adversely affect compactibility, especially in direct

compression. Moreover, intragranular starch in wet granulations is not as effective as dry

starch.

Mechanism of Superdisintegrants

There are four major mechanisms for tablets disintegration as follows

Swelling

Perhaps the most widely accepted general mechanism of action for tablet

disintegration is swelling. Tablets with high porosity show poor disintegration due

to lack of adequate swelling force. On the other hand, sufficient swelling force is

exerted in the tablet with low porosity. It is worthwhile to note that if the packing

fraction is very high, fluid is unable to penetrate in the tablet and disintegration is

again slows down.

Porosity and capillary action (Wicking)

Disintegration by capillary action is always the first step. When we put the tablet

into suitable aqueous medium, the medium penetrates into the tablet and replaces

the air adsorbed on the particles, which weakens the intermolecular bond and

breaks the tablet into fine particles. Water uptake by tablet depends upon

hydrophilicity of the drug/excipient and on tableting conditions. For these types of

disintegrants maintenance of porous structure and low interfacial tension towards

aqueous fluid is necessary which helps in disintegration by creating a hydrophilic

network around the drug particles.

Introduction


Due to disintegrating particle/particle repulsive forces

Another mechanism of disintegration attempts to explain the swelling of tablet

made with nonswellable disintegrants. Guyot-Hermann has proposed a particle

repulsion theory based on the observation that nonswelling particle also cause

disintegration of tablets. The electric repulsive forces between particles are the

mechanism of disintegration and water is required for it. Researchers found that

repulsion is secondary to wicking.

Due to deformation

During tablet compression, disintegrated particles get deformed and these

deformed particles get into their normal structure when they come in contact with

aqueous media or water. Occasionally, the swelling capacity of starch was

improved when granules were extensively deformed during compression. This

increase in size of the deformed particles produces a breakup of the tablet.

Method of Addition of Disintegrants

The ideal disintegrant should have the following characteristics:

Poor solubility

Poor gel formation

Good hydration capacity

Good molding and flow properties

No tendency to form complexes with the drugs

Disintegrants are essentially added to tablet granulation for causing the

compressed tablet to break or disintegrate when placed in aqueous environment. There

are two methods of incorporating disintegrating agents into the tablet:

Internal Addition (Intragranular)

External Addition (Extragranular)

Partly Internal and External

Introduction


In external addition method, the disintegrant is added to the sized granulation with

mixing prior to compression. In Internal addition method, the disintegrant is mixed with

other powders before wetting the powder mixtures with the granulating fluid. Thus the

disintegrant is incorporated within the granules. When these methods are used, part of

disintegrant can be added internally and part externally. This provides immediate

disruption of the tablet into previously compressed granules while the disintegrating

agent within the granules produces further erosion of the granules to the original powder

particles. The two step method usually produces better and more complete disintegration

than the usual method of adding the disintegrant to the granulation surface only.

Factors affecting action of disintegrants

Percentage of disintegrants present in the tablets.

Types of substances present in the tablets.

Combination of disintegrants.

Presence of surfactants.

Hardness of the tablets.

Nature of Drug substances.

Mixing and Screening.

Because of the increased demands for improved dissolution requirements, there

are currently, a new generation of Superdisintegrants. These newer substances are

more effective at lower concentrations with greater disintegrating efficiency and

mechanical strength. On contact with water the superdisintegrants swell, hydrate,

change volume or form and produce a disruptive change in the tablet. Effective

superdisintegrants provide improved compressibility, compatibility and have no

negative impact on the mechanical strength of formulations containing high-dose drugs.

They are widely used in wet granulation and direct compression applications.

Introduction


Classification of superdisintegrants

Structural type

(NF name) Description

Trade name

(manufacturer)

Modified starches (Sodium

starch glycolate, NF)

Sodium carboxymethyl

starch; the carboxymethyl

groups induces

hydrophilicity and cross-

linking reduces solubility.

Explotab(Edward Mendell

Co.), Primojel

(Generichem Corp.),

Tablo (Blanver, Brazil)

Modified cellulose

(Croscarmellose, NF)

Sodium carboxymethyl

cellulose which has been

cross-linked to render the

material insoluble.

AcDiSol (FMC Corp.),

Nymcel ZSX (Nyma,

Netherlands), Primellose

(Avebe, Netherlands)

Solutab (Blanver, Brazil)

Cross-linked poly-

vinylpyrrolidone

(Crospovidone, NF)

Cross-linked

polyvinylpyrrolidone; the

high molecular weight and

cross-linking render the

material insoluble in water.

Crospovidone M (BASF

Corp.), Kollidon CL

(BASF Corp.),

Polyplasdone XL (ISP

Corp.)

Three major groups of compounds have been developed which swell to many

times their original size when placed in water while producing minimal viscosity

effects.19

1. Modified starches - Sodium Carboxymethyl Starch (Chemically treated Potato Starch)

i.e. Sodium Starch Glycolate (Explotab, Primogel)

Mechanism of Action: Rapid and extensive swelling with minimal gelling.

Effective Concentration: 4-6 %. Above 8 %, disintegration times may actually increase

due to gelling and its subsequent viscosity producing effects.

Introduction


2.Cross-linked polyvinylpyrrolidone - water insoluble and strongly hydrophilic.

i.e. Crospovidone (Polyplasdone XL, Kollidon CL)

Mechanism of Action: Water wicking, swelling and possibly some deformation recovery.

Effective Concentration: 2-4 %

3.Modified cellulose- Internally cross-linked form of Sodium carboxymethyl cellulose.

i.e. Ac-Di-Sol (Accelerates Dissolution), Nymcel

Mechanism of Action: Wicking due to fibrous structure, swelling with minimal gelling.

Effective Concentration: 1-3 % (Direct Compression), 2-4 % (Wet Granulation).

Advantages

Effective in lower concentrations than starch.

Less effect on compressibility and flow ability.

More effective intragranularly.

Disadvantages

More hygroscopic (may be a problem with moisture sensitive drugs).

Some are anionic and may cause some slight in vitro binding with cationic drugs

(not a problem in vivo).

Packaging of dispersible tablets

Some of the dispersible tablets are stable during storage, e.g. for 2 years or even

3 years in conventional packaging and these type of dosage forms are stored in HDPE

bottles, blister and strip packs.

Some of the examples of dispersible tablets

Aspirin dispersible tablet

Cefadroxil dispersible tablet

Fast dispersible Ibuprofen tablet

Piroxicam dispersible tablet

Introduction


Cefpodoxime Proxetil dispersible tablet

Cefixime dispersible Tablet

Rifampicin and Isoniazid dispersible tablets

http://www.alibaba.com/product/surajdistributors-101261411-100610547/Cefixime_100_Mg_Dispersible_Tablet.htmlhttp://www.who.int/entity/medicines/services/expertcommittees/pharmprep/Rif_Iso_Pyraz_dispersTabs_monoRev1_QAS07_222.pdf

Literature Review


LITERATURE REVIEW

By Suresh Bandari et al. (2008) 2 Review article: Oral drug delivery

remains the preferred route for administration of various drugs. Recent

developments in the technology have prompted scientists to develop orally

disintegrating tablets (ODTs) with improved patient compliance and

convenience. ODTs are solid unit dosage forms which disintegrate or

dissolve rapidly in the mouth without chewing and water. It describes the

various formulation aspects, disintegrants employed and technologies

developed for ODTs, along with various excipients, evaluation tests,

marketed formulations, and drugs explored in this field.

C.Mallikarjuna setty et al. (Apr 2008) 15 Development of fast dispersible

aceclofenac tablets: effect of functionally of super disintegrants.

Disintegration time and dissolution parameters decreased with increase in the

level of croscarmellose sodium.

D M Patel et al. (Feb 2008) 14 The purpose of thes investigation was to

develop fast dissolving tablets of Etoricoxib. Granules containing Etoricoxib,

menthol, crospovidone, aspartame and mannitol were prepared by wet

granulation technique. Menthol was sublimed from the granules by exposing

the granules to vaccum. The porous granules were then compressed in to

tablets. The tablets were evaluated for percentage friability and disintegration

time. Optimization of fast dissolving Etoricoxib tablets prepared by

sublimation technique. The dissolving tablets with improved etoricoxib

dissolution could be prepared by sublimation of tablet containing suitable

subliming agent.

Shailesh shatma et al. (Jan 2008) 11 Fast dissolving tablets (FDT)

promethazine theoclate were prepared by direct compression method after

incorporating superdisintegrants Ac-Di-Sol, SSG and Crospovidone in

Literature Review


different concentrations. Formulation and characterization of fast-dissolving

tablets of promethazine theoclate with USP type-II apparatus.

S.Jacob et al. (Oct 2007) 13 Novel co-processed excipients of mannitol and

microcrystalline cellulose for preparing fast dissolving tablets of glipizide

Using spray dring technique. Improves the fast dissolving tablet could be

prepared by the co-processed mixture of microcrystalline cellulose and

mannitol.

Sheetal malke et al. (Apr 2007) 12

Formulation and evaluation of

oxcarbazepine fast dissolving tablets. It prepared with Avicel 102 as diluent

& Ac-Di-Sol as a superdisintegrants by wet granulation process. All the

formulations were evaluated for characteristics such as Hardness, Friability,

Weight variation, Wetting ability, Disintegration time and Dissolution rate. A

modified disintegration method was used for studying disintegration. Since

the drug is poorly water soluble, drug release was tested in various media and

effect of surfactant on drug release was studied.

Jack Y. Zheng et al23 developed the purpose of this study is to assess the

feasibility for taste masking and comparison of taste intensity during

formulation development using a multichannel taste sensor system (e-

Tongue). Taste-masking efficiency was evaluated using quinine as a bitter

model compound and a sweetener, acesulfame K, as a bitterness inhibitor. the

bitterness inhibition of quinine by using other known taste-masking

excipients including sodium acetate, NaCl, Prosweet flavor, and

Debittering powder or soft drinks could be detected by the e-Tongue. These

results further suggest that the e-Tongue should be useful in a taste-masking

evaluation study on selecting appropriate taste-masking excipients for a

solution formulation or a reconstitution vehicle for a drug-in-bottle

formulation. Based on the group distance, the relative intensity of bitterness

for these compounds could be ranked in the following order: ranitidine

Literature Review


HCl > prednisoloneNa > quinine HCl phenylthiourea > paracetamol

sucrose octaacetate > caffeine. In conclusion, the multichannel taste sensor

or e-Tongue may be a useful tool to evaluate taste-masking efficiency for

solution formulations and to compare bitterness intensity of formulations and

drug substances during pharmaceutical product development.

Omaima A. Sammour et.al (2006)16 investigate the increase in the solubility

and dissolution rate of Rofecoxib by the preparation of its solid dispersion

with PVP K -30(1:9) using Solvent evaporation method. In an attempt to

construct a statistical model for the prediction of disintegration time and

percentage friability 32

randomized full and reduced factorial design was

used. The obtained results showed that dispersion of the drug in the polymer

considerably enhanced the dissolution rate.

Mishra D.N. et.al.(2005)17 Carried out formulation of rapidly disintegrating

tablets of meloxicam using super disintegrates like sodium starch

glycolate, Ac-di-sol and Low molecular weight HPMC. The disintegration

time in the oral cavity was tested And was found to be around 1 minute. It

was concluded that rapidly disintegrating tablets with proper hardness

rapidly disintegrates in the oral cavity with enhanced Dissolution rate.

Sheftell FD et.al (2005)18 developed fast disintegrating / Rapid release

Formulation of Sumatriptan to enhance tablet disintegration and drug

dispersion and potentially, improve absorption. Two studies were conducted

comparing the time to onset of relief from moderate or severe migraine pain

with the fast disintegrating / Rapid Release Formulation of Sumatriptan

tablets 50 and 100 mg and placebo. Using a personal digital assistant,

patients recorded the time of dosing and the at which pain severity reached

none that or mild in real time so that the time to onset of relief could be

measured as a continuous variable. Results shown that Sumatriptan tablets in

a fast disintegrating / Rapid release formulation were effective for the acute

Literature Review


treatment of moderate to severe migraine pain, were generally well tolerated

and achieved an onset of pain relief as early as 20 min. for - 100 mg and as

early as 30 min.for 50 mg.

Mukesh G. et.al. (2004)19 Formulates mouth dissolving tablet of

Nimesulide. Granules containing Nimesulide, camphor, crospovidone and

lactose were prepared by wet Direct Compression technique. Camphor was

sublimed from the dried granules by exposure by vacuum. The porous

granules were then compressed and evaluated. The result for obtaining a

rapidly disintegrating dosage forms, tablets should be prepared using an

optimum concentration of camphor and a higher percentage of crospovidone.

Yourong Fu et.al (2004)20 conducted comprehensive review of current

technologies in making fast dissolving tablet. Mannose was chosen as the

best candidate for the investigation. The mechanisms of fast dissolution of

mannose tablets were studied. The strength of mannose tablets was

improved by the moisture treatment process. Poly (acrylic acid), super

porous hydrogel (SPH) particles showed a high swelling property in various

aqueous solutions and had a very good compressibility and compatibility.

The effect of SPH particles on disintegration time and hardness of fast

dissolving tablet were compared to common super disintegrates such as

sodium starch glycolate and carboxymethyl cellulose sodium. The addition

of SPH significantly decreased the disintegration time of FDT.S but had a

negative impact on tensile strength. The results indicates PAA SPH is a

promising super disintegrates for making FDTS.

Mishra et al21 assessed the suitability of spray dried excipient base in the

formulation of oral disintegrating tablets of valdecoxib and metoclopramide.

Superdisintegrants (such as Ac-Di-Sol, Kollidon CL, sodium starch

glycolate), diluent (mannitol) along with sweetening agent (aspartame) were

used in the formulation of tablets. Using the same excipients, the tablets were

Literature Review


prepared by direct compression and were evaluated in the similar way.

Maximum drug release and minimum disintegrating time were observed with

Kollidon CL excipient base as compared to tablets prepared by direct

compression, showing the superiority of the spray dried excipient base

technique over direct compression technique

Moen and Keating et al22 developed a new fast-disintegrating sumatriptan

tablet with the goal of speeding absorption and onset of effect compared with

standard sumatriptan tablets. Compared with placebo, pain relief was

significantly greater with sumatriptan fast disintegrating tablets 100mg at 25

and 17 minutes following administration and with sumatriptan fast

disintegrating tablets 50mg at 50 and 30 minutes following administration, to

severe migraine.

Aim and objective

Dept of Pharmaceutics, Annai veilankannis pharmacy college, chennai

34

AIM AND OBJECTIVE

The aim is to develop and formulate PREDNISOLONE SODIUM

PHOSPHATE Orally Disintegrating tablets using different concentrations of taste

masking and enteric coating materials comparable to the innovator product with

better stability,high product feasibility,and excellent patient compatability.

The Objective of present study is to mask the bitter taste of the API and

prepare a Orally disintegrating tablets using taste masking materials, enteric

coating materials and super disintegrants which is pharmaceutically equivalent to

the Innovator product.

Plan of Work


PLAN OF WORK

To carry out a brief literature review.

To do Pre-formulation studies:

1) API- Tap density, bulk density, angle of repose and compressibility index.

2) BLEND- Tap density, bulk density, angle of repose and compressibility

index.

To Formulate of PREDISOLONE Sodium Phosphate Orally Disintegrated

Tablets.

To Evaluate PREDISOLONE Sodium Phosphate Orally Disintegrated

Tablets for Disintegration time and Dissolution study.

Selection of best formulation on the basis of Disintegration time and In-vitro

drug release.

To compare the best formulation with that of the innovator.

Materials and Methods


MATERIALS AND METHODS

INSTRUMENT LIST.

Instruments Supplier/Manufacturer

Compression machine Rimek minipress

Hot air oven Eltek motors, Mumbai

RMG mixer Sreenex machines pvt. Limited, Hyderabad

Sieves Jayanth test sieves. Mumbai.

Balances Citizen scale pvt. Limited, Thane.

Density tester Electrolab ,Mumbai

Disintegration apparatus Electrolab, Mumbai

Dissolution apparatus Electrolab, Mumbai

HPLC Waters India pvt. limited,

Hardness tester Dr.Schleuniger pharmatron,U S A.

Friabilator Electrolab, Mumbai

Helium lamp (LOD) Metteler- Toledo



MATERIALS LIST.

Materials Supplier/Manufacturer

Prednisolone sodium phosphate IPCA Laboratories

Avicel PH101 FMC Polymers

Poly ethylene Glycol 4000 BASF Corporation

Ethyl cellulose 4CPS The DOW chemical company

Mannitol spray dried SPI polyol, 321, new castle.

Eudragit EPO M/s. DEGUSSA

Eudragit L100 M/s. DEGUSSA

Crospovidone XL-10 M/s. ISP Technologies

Ethyl cellulose The DOW chemical company

Aspartame Neutrasweet pharma agencies

Sodium Bicarbonate Merk Chemicals

Citric acid Merk Chemicals

Aerosil M/s. DEGUSSA

Mint flavors Pan aroma, Chennai



METHODS

Innovator Product details:

Innovator product details including their manufacturer name, description, physical

parameters and dissolution profile were given in the following table

Innovator Product details:

Name of the product ORAPRED 30mg

Manufacturer name Alliant Pharmaceuticals Alpharetta, GA

30022,USA.

Color White

Description white, flat faced, beveled tablets, debossed with

ORA on one side and 30 on the other.

Package They are supplied as 48 tablets per carton. Each

carton has 8 cards containing 6 tablets.

Physical parameters of Innovator product:

Parameters 30mg

Weight of the tablet (mg) 605

Thickness (mm) 5.14

Hardness (kp) 3.08

Disintegration time (sec) 26

Dispersion time (sec) 60



PREFORMULATION STUDIES6:

Drug-excipient compatibility studies:

The proper design and the formulation of a dosage form require consideration

of the physical, chemical and biological characteristics of the drug and

excipients used in fabricating the product. The drug and excipients must be

compatible with one another to produce a product that is stable, efficacious,

attractive, easy to administer and safe.

The compatibility studies provide the framework for the drugs combination

with excipients in the fabrication of the dosage form. The study was carried

out to establish that the therapeutically active drug has not undergone any

changes, after it has been subjected to processing steps during formulation of

tablets.

Compatibility studies were carried out by mixing definite proportions of drug

and excipient and kept in glass vials, which are stored at 55C (2 weeks) and

402C/755 % RH(4 weeks).

Physical parameters of blend:

The following evaluation parameters studies were performed for the

Prednisolone sodium Phosphate.

Sieve Analysis:

Pass a define mass of the sample through various sieves and calculate the

percentage of retained powder and fines passed through sieves.

Weight of the powder

Percentage of powder retained = ----------------------------------- X 100

Total weight of the powder

Bulk density:

It is the ratio between a given mass of powder and its bulk volume.



Mass of powder

Bulk density = -----------------------------------

Total weight of the powder

A given quantity of the powder is transferred to the measuring cylinder and it

is tapped mechanically either manually or mechanical device till a constant volume is

obtained. This volume is bulk volume (v) and it includes the true volume of the

powder and void space among the powder particles.

Angle of repose:

Angle of repose is defined as the maximum angle possible between the

surface of pile of powder and the horizontal plane. The granule mass should allowed

to flow out of the funnel orifice on a plane paper kept on the horizontal surface. This

forms a pile of granules on the paper.

Tan = h/r = tan-1

(h/r)

Where, h= height of the pile

r= radius of the pile

Tapped density:

Tapped density is defined as the ratio between weight of the sample powder

taken and the tapped volume.

Tapped density(t) = M/Vf

Where , M = weight of sample powder taken

Vf = tapped volume

Compressibility index /Carrs index:



Based on the apparent bulk density and the tapped density, the percentage

compressibility index of the powder was determined by using the following formula.

Tapped density-Bulk density

Compressibility index = ----------------------------------------- X 100

Tapped density

Hausner ratio:

By calculating tapped density and bulk density, the Hausner ratio can be

calculated.

Hausner ratio = t / o

Where, t = tapped density

o = bulk density

Flow Properties of Powder.

S. No Angle of repose Carrs index Hausners

ratio Properties

1 25-30 5-12 1.00-1.11 Free Flowing

2 30-35 12-16 1.12-1.18 Good

3 35-40 18-21 1.19-1.25 Fair

4 40-55 23-35 1.35-1.45 Poor

5 55-65 33-38 1.46-1.59 Very poor

6 >65 >40 >1.60 Extremely poor

There are various in-process control parameters should be performed. They are

During tablet compression:

o Appearance

o Average weight

o Weight uniformity

o Hardness



o Thickness

o Disintegration time

o Dissolution8

Method development:

Formulation of Prednisolone orally disintegrating tablets by method of taste

masking with PEG 4000, Ethyl cellulose, Eudragit EPO and Eudragit L100. Tablets

can be formulated by wet granulation method.

Drug profile


DRUG PROFILE

PREDNISOLONE SODIUM PHOSHATE

Chemical name: pregna-1, 4-diene-3,20-dione,11, 17-dihydroxy-21-

(phosphonooxy), disodium salt(11)-

.

The empirical formula: C21H27Na2O8P;

The molecular weight: 484.39

Physical properties

Color: White or slightly yellowish

State/form: Friable granules or powder

Solubility: It is freely soluble in water; soluble in methanol; slightly soluble in

alcohol and in chloroform; and very slightly soluble in acetone and in dioxane.

Pharmacokinetics:

Absorption: Absorbed from GIT

Bioavailability: Found to be about 62%. The fraction of the dose recovered in the

urine as the hydroxylated metabolites of prednisone and prednisolone was lower after

the oral prednisone dose, suggesting that poor absorption of prednisone was the main

cause of the low bioavailability.

Plasma binding: 70-90%

Elimination: Eliminated from the plasma with a half-life of 2 to 4 hours. It is

metabolized mainly in the liver and excreted in the urine as sulfate and glucuronide

conjugates.

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Drug profile


Dose: Available in strengths containing 13.4 mg, 20.2 mg, and 40.3 mg prednisolone

sodium phosphate (equivalent to 10 mg, 15 mg, or 30 mg prednisolone base,

respectively).

Pharmacodynamics:

Pharmacological Category: Glucocorticoid

Clinical Pharmacology4:

Naturally occurring glucocorticoids (hydrocortisone), which also have salt-

retaining properties, are used as replacement therapy in adrenocortical deficiency

states. Their synthetic analogs are primarily used for their potent anti-inflammatory

effects in disorders of many organ systems.

Prednisolone is a synthetic adrenocortical steroid drug with predominantly

glucocorticoid properties. Some of these properties reproduce the physiological

actions of endogenous glucocorticosteroids, but others do not necessarily reflect any

of the adrenal hormones normal functions; they are seen only after administration of

large therapeutic doses of the drug. The pharmacological effects of prednisolone

which are due to its glucocorticoid properties include: promotion of gluconeogenesis;

increased deposition of glycogen in the liver; inhibition of the utilization of glucose;

anti-insulin activity; increased catabolism of protein; increased lipolysis; stimulation

of fat synthesis and storage; increased glomerular filtration rate and resulting increase

in urinary excretion of urate (creatinine excretion remains unchanged); and increased

calcium excretion.

Depressed production of eosinophils and lymphocytes occurs, but

erythropoiesis and production of polymorphonuclear leukocytes are stimulated.

Inflammatory processes (edema, fibrin deposition, capillary dilatation, migration of

leukocytes and phagocytosis) and the later stages of wound healing (capillary

proliferation, deposition of collagen, cicatrization) are inhibited.

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Drug profile


Prednisolone can stimulate secretion of various components of gastric juice.

Suppression of the production of corticotropin may lead to suppression of

endogenous corticosteroids. Prednisolone has slight mineralocorticoid activity,

whereby entry of sodium into cells and loss of intracellular potassium is stimulated.

This is particularly evident in the kidney, where rapid ion exchange leads to sodium

retention and hypertension.

Prednisolone is rapidly and well absorbed from the gastrointestinal tract

following oral administration. Prednisolone is 70-90% protein-bound in the plasma

and it is eliminated from the plasma with a half-life of 2 to 4 hours. It is metabolized

mainly in the liver and excreted in the urine as sulfate and glucuronide conjugates.

The systemic availability, metabolism and elimination of prednisolone after

administration of single weight-based doses (0.8 mg/kg) of intravenous (IV)

prednisolone and oral prednisone were reported in a small study of 19 young (23 to

34 years) and 12 elderly (65 to 89 years) subjects. Results showed that the systemic

availability of total and unbound prednisolone, as well as interconversion between

prednisolone and prednisone were independent of age. The mean unbound fraction of

prednisolone was higher, and the steady-state volume of distribution (Vss) of

unbound prednisolone was reduced in elderly patients. Plasma prednisolone

concentrations were higher in elderly subjects, and the higher AUCs of total and

unbound prednisolone were most likely reflective of an impaired metabolic clearance,

evidenced by reduced fractional urinary clearance of 6b-hydroxyprednisolone.

Despite these findings of higher total and unbound prednisolone concentrations,

elderly subjects had higher AUCs of cortisol, suggesting that the elderly population is

less sensitive to suppression of endogenous cortisol or their capacity for hepatic

inactivation of cortisol is diminished.

Oral administration of single doses of 30 mg prednisolone base equivalent of

Orapred ODT and Pediapred Solution to 21 adult volunteers yielded comparable

pharmacokinetic data:

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Drug profile

Dept of Pharmaceutics, Annai veilankannis pharmacy college, chennai

formulation and evaluation of …repository-tnmgrmu.ac.in/1185/1/elmuzamil abbkar elhaj...

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